Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation

Symptoms of neurological diseases emerge through the dysfunction of neural circuits whose diffuse and intertwined architectures pose serious challenges for delivering therapies. Deep brain stimulation (DBS) improves Parkinson's disease symptoms acutely but does not differentiate between neuronal circuits, and its effects decay rapidly if stimulation is discontinued. Recent findings suggest that optogenetic manipulation of distinct neuronal subpopulations in the external globus pallidus (GPe) provides long-lasting therapeutic effects in dopamine-depleted (DD) mice. We used synaptic differences to excite parvalbumin-expressing GPe neurons and inhibit lim-homeobox-6-expressing GPe neurons simultaneously using brief bursts of electrical stimulation. In DD mice, circuit-inspired DBS provided long-lasting therapeutic benefits that far exceeded those induced by conventional DBS, extending several hours after stimulation. These results establish the feasibility of transforming knowledge of circuit architecture into translatable therapeutic approaches.

Automated summary

This study demonstrates that manipulating distinct neural subpopulations in the GPe through optogenetics can provide long-lasting therapeutic effects in dopamine-depleted mice, surpassing the effects of traditional DBS. By using synaptic differences and brief bursts of electrical stimulation to excite and inhibit different types of GPe neurons, the circuit-inspired DBS produced sustained therapeutic benefits extending beyond conventional DBS.